Mitogen-activated protein (MAP) kinases belong to a highly conserved family of Ser-Thr protein kinases in the human kinome and have diverse roles in broad physiological functions. The 4 ...best-characterized MAP kinase pathways, ERK1/2, JNK, p38, and ERK5, have been implicated in different aspects of cardiac regulation, from development to pathological remodeling. Recent advancements in the development of kinase-specific inhibitors and genetically engineered animal models have revealed significant new insights about MAP kinase pathways in the heart. However, this explosive body of new information also has yielded many controversies about the functional role of specific MAP kinases as either detrimental promoters or critical protectors of the heart during cardiac pathological processes. These uncertainties have raised questions on whether/how MAP kinases can be targeted to develop effective therapies against heart diseases. In this review, recent studies examining the role of MAP kinase subfamilies in cardiac development, hypertrophy, and survival are summarized.
Metabolic remodeling is a hall-mark of cardiac maturation and pathology. The switch of substrate utilization from glucose to fatty acid is observed during post-natal maturation period in developing ...heart, but the process is reversed from fatty acids to glucose in the failing hearts across different clinic and experimental models. Majority of the current investigations have been focusing on the regulatory mechanism and functional impact of this metabolic reprogramming involving fatty acids and carbohydrates. Recent progress in metabolomics and transcriptomic analysis, however, revealed another significant remodeled metabolic branch associated with cardiac development and disease, i.e. Branched-Chain Amino Acid (BCAA) catabolism. These findings have established BCAA catabolic deficiency as a novel metabolic feature in failing hearts with potentially significant impact on the progression of pathological remodeling and dysfunction. In this review, we will evaluate the current evidence and potential implication of these discoveries in the context of heart diseases and novel therapies.
This article is part of a Special Issue entitled: The role of post-translational protein modifications on heart and vascular metabolism edited by Jason R.B. Dyck & Jan F.C. Glatz.
•BCAA catabolic activity is dynamically regulated in cardiac development and diseases.•BCAA catabolic defects are associated with pathological remodeling and dysfunction.•Accumulation of BCAA and catabolic products may contribute to disease progression in the heart.•BCAA catabolic flux modulation is a potential therapeutic approach for heart failure.
Cardiomyocyte hypertrophy is an integral part of cardiac remodeling that occurs under physiological or pathological stresses. It can lead to heart failure in a pathological form or oppose functional ...deterioration in a compensatory one. The mechanisms underlying an adaptive outcome of hypertrophy are ill defined. In this issue of the JCI, Kashihara et al. explored the role of the Yes-associated protein 1 (YAP) transcription factor in the heart, using cell culturing and mouse models. YAP activity was found to be associated with changes in genes of the glycolytic and auxiliary pathways under stress. Notably, YAP upregulated glucose transporter 1 (GLUT1), and inhibition of GLUT1 blocked YAP-induced hypertrophy but worsened heart function. These findings suggest that YAP is a regulator of metabolic reprogramming in the heart during compensatory hypertrophy. This insight may help in the development of future therapies for heart failure.
Among the myriad of intracellular signaling networks that govern the cardiac development and pathogenesis, mitogen-activated protein kinases (MAPKs) are prominent players that have been the focus of ...extensive investigations in the past decades. The four best characterized MAPK subfamilies, ERK1/2, JNK, p38, and ERK5, are the targets of pharmacological and genetic manipulations to uncover their roles in cardiac development, function, and diseases. However, information reported in the literature from these efforts has not yet resulted in a clear view about the roles of specific MAPK pathways in heart. Rather, controversies from contradictive results have led to a perception that MAPKs are ambiguous characters in heart with both protective and detrimental effects. The primary object of this review is to provide a comprehensive overview of the current progress, in an effort to highlight the areas where consensus is established verses the ones where controversy remains. MAPKs in cardiac development, cardiac hypertrophy, ischemia/reperfusion injury, and pathological remodeling are the main focuses of this review as these represent the most critical issues for evaluating MAPKs as viable targets of therapeutic development. The studies presented in this review will help to reveal the major challenges in the field and the limitations of current approaches and point to a critical need in future studies to gain better understanding of the fundamental mechanisms of MAPK function and regulation in the heart.
The high sodium content in Xinjiang coal ash induces severe fouling and slagging in pulverized coal furnaces. To solve these problems, many people have reported to use silicon–aluminum additives. In ...this paper, the effects of silicon–aluminum additives (SiO2, kaolin, and fly ash) on ash fusion characteristic, mineral transformation, and sodium emission were investigated. The results showed that the ash fusion temperatures (AFTs) manifested a pattern of decrease first and increase later along with an increasing in silicon–aluminum additive ratios. To achieve higher AFTs than that of raw coal ash, the blending proportion of silicon–aluminum additives is recommended as high as 9%. The causes for these results were explored. When the proportion of the additives was 3%, Ertixiite (Na2Si2O5), nepheline (NaAlSi3O8), lazurite (Na7Al6Si6O24S3) and hauyne (Na6Ca2Al6Si6O24(SO4)2), were formed at 1150°C. These species with low melting temperatures are flux minerals and lower ash fusion temperature, resulting in the lowest AFTs. This is the main cause of lower ash fusion point in the case of lower blending ratios. Moreover, almost all of the tested additives show the capability of capturing sodium, in which, the capturing capability of SiO2 is the best. For sodium capture capacity of the three additives under most tested conditions, the optimum temperature was around 1000°C.
Recent studies implicate a strong association between elevated plasma branched-chain amino acids (BCAAs) and insulin resistance (IR). However, a causal relationship and whether interrupted BCAA ...homeostasis can serve as a therapeutic target for diabetes remain to be established experimentally. In this study, unbiased integrative pathway analyses identified a unique genetic link between obesity-associated IR and BCAA catabolic gene expression at the pathway level in human and mouse populations. In genetically obese (
) mice, rate-limiting branched-chain α-keto acid (BCKA) dehydrogenase deficiency (i.e., BCAA and BCKA accumulation), a metabolic feature, accompanied the systemic suppression of BCAA catabolic genes. Restoring BCAA catabolic flux with a pharmacological inhibitor of BCKA dehydrogenase kinase (BCKDK) ( a suppressor of BCKA dehydrogenase) reduced the abundance of BCAA and BCKA and markedly attenuated IR in
mice. Similar outcomes were achieved by reducing protein (and thus BCAA) intake, whereas increasing BCAA intake did the opposite; this corroborates the pathogenic roles of BCAAs and BCKAs in IR in
mice. Like BCAAs, BCKAs also suppressed insulin signaling via activation of mammalian target of rapamycin complex 1. Finally, the small-molecule BCKDK inhibitor significantly attenuated IR in high-fat diet-induced obese mice. Collectively, these data demonstrate a pivotal causal role of a BCAA catabolic defect and elevated abundance of BCAAs and BCKAs in obesity-associated IR and provide proof-of-concept evidence for the therapeutic validity of manipulating BCAA metabolism for treating diabetes.
Single-cell RNA sequencing (scRNA-seq) technologies are poised to reshape the current cell-type classification system. However, a transcriptome-based single-cell atlas has not been achieved for ...complex mammalian systems. Here, we developed Microwell-seq, a high-throughput and low-cost scRNA-seq platform using simple, inexpensive devices. Using Microwell-seq, we analyzed more than 400,000 single cells covering all of the major mouse organs and constructed a basic scheme for a mouse cell atlas (MCA). We reveal a single-cell hierarchy for many tissues that have not been well characterized previously. We built a web-based “single-cell MCA analysis” pipeline that accurately defines cell types based on single-cell digital expression. Our study demonstrates the wide applicability of the Microwell-seq technology and MCA resource.
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•Development of Microwell-seq, a high-throughput and low-cost scRNA-seq platform•Construction of a single-cell mouse cell atlas (scMCA) covering major cell types•Characterization of cellular heterogeneity with minimal batch effect•Characterization of cross-tissue cellular network at the single-cell level
Development of Microwell-seq allows construction of a mouse cell atlas at the single-cell level with a high-throughput and low-cost platform.
Small interfering RNA (siRNA) holds inherent advantages and great potential for treating refractory diseases. However, lack of suitable siRNA delivery systems that demonstrate excellent circulation ...stability and effective at‐site delivery ability is currently impeding siRNA therapeutic performance. Here, a polymeric siRNA nanomedicine (3I‐NM@siRNA) stabilized by triple interactions (electrostatic, hydrogen bond, and hydrophobic) is constructed. Incorporating extra hydrogen and hydrophobic interactions significantly improves the physiological stability compared to an siRNA nanomedicine analog that solely relies on the electrostatic interaction for stability. The developed 3I‐NM@siRNA nanomedicine demonstrates effective at‐site siRNA release resulting from tumoral reactive oxygen species (ROS)‐triggered sequential destabilization. Furthermore, the utility of 3I‐NM@siRNA for treating glioblastoma (GBM) by functionalizing 3I‐NM@siRNA nanomedicine with angiopep‐2 peptide is enhanced. The targeted Ang‐3I‐NM@siRNA exhibits superb blood–brain barrier penetration and potent tumor accumulation. Moreover, by cotargeting polo‐like kinase 1 and vascular endothelial growth factor receptor‐2, Ang‐3I‐NM@siRNA shows effective suppression of tumor growth and significantly improved survival time of nude mice bearing orthotopic GBM brain tumors. New siRNA nanomedicines featuring triple‐interaction stabilization together with inbuilt self‐destruct delivery ability provide a robust and potent platform for targeted GBM siRNA therapy, which may have utility for RNA interference therapy of other tumors or brain diseases.
A triple‐interaction‐stabilized small interfering RNA (siRNA) nanomedicine shows potent stability both in vitro and in vivo. When it encounters a reactive oxygen species (ROS) stimulus inside a tumor, the “triple‐interaction” stabilization forces can be sequentially neutralized, resulting in effective siRNA release. Moreover, on modification with angiopep‐2 peptide, the triple‐interaction‐stabilized siRNA nanomedicine demonstrates robust orthotopic glioblastoma combinational RNA interference therapy.
Epigenetic reprogramming is a critical process of pathological gene induction during cardiac hypertrophy and remodeling, but the underlying regulatory mechanisms remain to be elucidated. Here we ...identified a heart-enriched long noncoding (lnc)RNA, named cardiac-hypertrophy-associated epigenetic regulator (Chaer), which is necessary for the development of cardiac hypertrophy. Mechanistically, Chaer directly interacts with the catalytic subunit of polycomb repressor complex 2 (PRC2). This interaction, which is mediated by a 66-mer motif in Chaer, interferes with PRC2 targeting to genomic loci, thereby inhibiting histone H3 lysine 27 methylation at the promoter regions of genes involved in cardiac hypertrophy. The interaction between Chaer and PRC2 is transiently induced after hormone or stress stimulation in a process involving mammalian target of rapamycin complex 1, and this interaction is a prerequisite for epigenetic reprogramming and induction of genes involved in hypertrophy. Inhibition of Chaer expression in the heart before, but not after, the onset of pressure overload substantially attenuates cardiac hypertrophy and dysfunction. Our study reveals that stress-induced pathological gene activation in the heart requires a previously uncharacterized lncRNA-dependent epigenetic checkpoint.
The World Health Organization (WHO) declared coronavirus disease 2019 (COVID-19) as a public health emergency of international concern as more than 15 million cases were reported by 24th July 2020. ...Angiotensin-converting enzyme 2 (ACE2) is a COVID-19 entry receptor regulating host cell infection. A recent study reported that ACE2 is expressed in cardiomyocytes. In this study, we aimed to explore if there are microRNA (miRNA) molecules which target ACE2 and which may be exploited to regulate the SARS-CoV-2 receptor. Our data reveal that both Ace2 mRNA and Ace2 protein levels are inhibited by miR-200c in rat primary cardiomyocytes and importantly, in human iPSC-derived cardiomyocytes. We report the first miRNA candidate that can target ACE2 in cardiomyocytes and thus may be exploited as a preventive strategy to treat cardiovascular complications of COVID-19.
•ACE2 is expressed in various cardiovascular cells including cardiomyocytes.•MicroRNA molecules can play an important role in ACE2 regulation.•MiR-200c can modulate ACE2 expression in both rat and human cardiomyocytes.
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